Recent studies indicate that hypothalamic astrocytes contribute to the central mechanism controlling the initiation of mammalian puberty. This contribution involves a complex array of cell-cell interactions initiated by at least two members of the epidermal growth factor (EGF) family of growth factors, transforming growth factor alpha (TGF`) and neuregulins (NRGs), produced in astrocytes. At puberty, hypothalamic synthesis of TGF` increases, becoming maximal on the day of the first preovulatory surge of gonadotropins. The increase in TGF` gene expression occurs in the absence of augmented levels of the TGF` receptor, EGFR/erbB-1, but it is accompanied by enhanced synthesis of erbB-4 and erbB-2, two of the NRG receptors expressed in hypothalamic astrocytes. In fact, hypothalamic expression of both of these receptors first increases, in a gonadal -independent manner, during late juvenile development. The initial peripubertal changes in TGF` and erbB-4 mRNA levels are followed by a more abrupt increase in erbB-2/neu receptor synthesis, which is limited to the day of first proestrus. ErbB-2/neu is thought to function as a common auxiliary subunit for the TGF` and NRG receptors. Blockade of erbB-2 synthesis via antisense oligodeoxynucleotides revealed that the erbB-2/neu receptor potentiates both erbB-1 and erbB-4-mediated signaling in hypothalamic astrocytes. ErbB-2 is also required for the timely initiation of puberty. The peripubertal changes in TGF`, erbB-2 and erbB-4 gene expression are facilitated by ovarian steroids. Of these, estrogen exerts at least part of its stimulatory effect via a direct action on hypothalamic astrocytes. Both TGF` and NRGs stimulate LHRH release via a paracrine mechanism involving activation of their cognate receptors in glial cells and the release of neuroactive substances in response to this activation. Prostaglandin E2 was identified as one of these bioactive molecules. cDNA fragments corresponding to portions of the genes encoding neuregulins and their erbB receptors in the rhesus monkey have been cloned and are being used to examine the developmental profile of these genes in the monkey hypothalamus. As focal activation of TGF` synthesis in the vicinity of LHRH neurons -- via grafting of cells genetically engineered to produce the growth factor -- advances the onset of puberty, it would appear that interactions between glial cells associated with the LHRH neuronal network may contribute significantly to the cell-cell mechanisms underlying the central control of sexual maturation in the female. This concept is strengthened by the finding that astrocytes in two human hypothalamic hamartomas causing sexual precocity are a significant source of TGF`. Thus, this glial regulatory system may be important for both the initiation of normal human puberty, and sexual precocity of central origin.